WO2018155922A1 - Composition, comprising ethyl ferulate as active ingredient, for allergic alleviation - Google Patents

Abstract

Disclosed is a composition, comprising ethyl ferulate as an active ingredient, for allergic alleviation. A composition according to an aspect of the present invention improves skin barrier functions and mast cell degranulation, which are major causes of allergic responses, and thus can effectively alleviate allergic responses. In addition, the composition of the present invention, when is recently co-used with a cosmetic composition, a pharmaceutical composition, and a food composition, which are substances in direct contact with the human body, can prevent or minimize allergic responses caused by the compositions.

Description

Allergy relief composition comprising ethyl ferulate as an active ingredient

The present disclosure discloses an allergy alleviation composition containing ethyl ferulate as an active ingredient.

Allergy refers to a pathological reaction caused by contact with allergen due to innate or acquired immune function abnormalities. Typical allergens include pollen, drugs, plant fibers, bacteria, fungi, house dust mites, food, dust, dyes, and chemicals. In recent years, there are also increasing cases of allergic diseases caused by various chemicals and natural extracts contained in cosmetics.

Representative allergic diseases include atopic dermatitis, bronchial asthma, allergic rhinitis, allergic keratitis and skin urticaria. Looking at the mechanism of allergic reaction, when allergens invade the living body, T-helper cells and B cells are sequentially activated to generate IgE. The generated IgE binds to the high-affinity IgE receptor on the mast cell membrane, and when allergens such as ticks and pollen bind to form a crosslink, the receptor aggregates. By crosslinking and aggregation of receptors, mast cells are activated to increase calcium ion concentration in the cytoplasm. The increase in calcium ion concentration acts on various cellular regulators such as cholesterol and cytoskeleton of the cell membrane to move the granules to the cell membrane and at the same time degranulates through phobia of granules, fusion of granules and fusion of granules and cell membranes. Causes Degranulation releases a chemical transfer material previously stored in mast cells such as histamine and releases newly synthesized prostaglandin-leukotriene. Chemotransmitters liberated by degranulation include NCF, ECF, which act as chemotactic factors of inflammatory cells such as eosinophils or neutrophils, in addition to histamine, serotonin, and leukotriene, which have the effects of vasodilation, vascular permeability, and contraction or secretion of bronchial smooth muscle. Allergic reactions occur due to PAF

Currently, as an anti-allergic drug, alkylamine, anti-IgE, etc. are used, but many side effects are severe, and the symptoms are only temporarily relieved rather than fundamentally eliminate the cause of allergy.

Therefore, there is a need for the development of new substances that can fundamentally improve allergic diseases, with fewer side effects and lasting effects.

[Preceding technical literature]

(Non-Patent Document 1) Hyun-Hee Kim, Role of Basophils in Allergic Inflammatory Mechanisms, Department of Pediatrics, Catholic University College of Medicine, Vol. 46, No. 6, 2003

In one aspect, an object of the present invention is to improve skin allergy.

In one aspect, an object of the present invention is to effectively improve skin troubles caused by allergy phenomenon.

In one aspect, the present invention provides an allergy alleviation composition comprising ethyl ferulate, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

In one aspect of the present invention, a composition comprising ethyl ferulate, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof as an active ingredient includes a skin barrier function, which is an important cause of an allergic reaction, By improving the degranulation response of mast cells, the allergic reaction can be effectively improved. In addition, in recent years, when used in combination with a cosmetic composition, a pharmaceutical composition and a food composition that is a material directly in contact with the human body, there is an advantage that it can prevent or minimize the allergic reaction caused by the compositions.

1 is a measure of the secretion amount of beta-hexosaminidase when treating the allergen-producing substance to mast cells after treating the composition of one aspect of the present invention.

Figure 2 is a diagram confirming the histamine secretion inhibitory effect when treating the allergen-inducing substance to mast cells after treating the composition of one aspect of the present invention.

Figure 3 is a diagram confirming the change in the expression of serine-palmitoyl convertase 1 when treated with a composition that is an aspect of the present invention to human keratinocytes.

Figure 4 is a diagram confirming the expression change of ceramide synthase 3 when the human keratinocytes are treated with the composition of one aspect of the present invention.

Hereinafter, the present invention will be described in detail.

In one aspect, the present invention is an allergy alleviation composition comprising ethyl ferulate, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

The ethyl ferulate, also called ethyl-4-hydroxy-3-methoxycinnamate, is a substance having the molecular formula C ₁₂ H ₁₄ O ₄ , molecular weight of 224.24 g / mol, Is the same as the formula (1).

[Formula 1]

As used herein, "isomers" specifically refer to optical isomers (e.g., essentially pure enantiomers, essentially pure diastereomers or mixtures thereof), as well as conformation isomers. ) (Ie, isomers that differ only in the angle of one or more chemical bonds), position isomers (especially tautomers) or geometric isomers (eg, cis-trans isomers).

As used herein, “essentially pure” means, when used in connection with an enantiomer or diastereomer, about 90% or more, specifically about 95% or more, of specific compounds, for example enantiomers or diastereomers, More specifically at least about 97% or at least about 98%, even more specifically at least about 99%, even more specifically at least about 99.5% (w / w).

As used herein, "pharmaceutically acceptable" means the approval of a government or equivalent regulatory body to use in animals, more specifically in humans, by avoiding significant toxic effects when used in conventional medicinal dosages. It can be received or approved, or listed in a pharmacopoeia or recognized as another general pharmacopeia.

As used herein, "pharmaceutically acceptable salts" means salts according to one aspect of the invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. The salt is formed from (1) an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like; Or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2,2,2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert Acid addition salts formed with organic acids such as butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; Or (2) salts formed when the acidic protons present in the parent compound are substituted.

As used herein, "prodrug" refers to a drug that modulates physical and chemical properties by chemically changing a drug, which itself does not exhibit physiological activity, but is originally produced by the action of a chemical or enzyme in the body after administration. The drug can be turned into a drug.

As used herein, "hydrate" refers to a compound to which water is bound, and is a broad concept including an inclusion compound having no chemical bonding force between water and the compound.

As used herein, the term "solvate" means a higher order compound produced between molecules or ions of a solute and molecules or ions of a solvent.

The composition can improve skin troubles caused by allergies. As used herein, "skin trouble" is meant to encompass cases where the skin is not in a normal state due to allergy.

As used herein, the term "skin" refers to a tissue covering the body surface of an animal, and is a broad concept including not only tissues covering the body surface such as the face or body, but also the scalp.

As used herein, the term "allergy" is the broadest concept that collectively refers to changes in the body that occur when the organism comes in contact with an alien substance (allergen) in response to changes in the body's response to the in vivo antibody. There is no restriction on the kind of the adventitious substance herein, specifically, pollen, drugs, vegetable fibers, bacteria, food, dyes or shoes

But may include, but is not limited to. The present specification does not limit specific parts of the body that show changes due to the adventitious substance.

In addition, allergic in the present specification is meant to include changes in the body appearing in response to changes in vivo response due to endogenous factors, such as hormonal changes, stress, emotional disorders, fatigue, lack of sleep.

The allergic diseases include edema, anaphylaxis, allergic rhinitis, allergic asthma, hay fever, Quincke's edema, allergic conjunctivitis ), Allergic keratitis, allergic dermatitis, atopic dermatitis, contact dermatitis, hives, pruritus, insect allergies, food allergies and It may be one or more selected from the group consisting of drug allergies, but is not limited thereto and includes all changes in the living body by the adventitious factor or the endogenous factor.

On the other hand, the skin is a representative organ that exhibits an immune response while retaining moisture in the body and performing an essential barrier function that protects internal invasion of external invading factors (antigens, infectious agents, etc.), and this barrier function has an overall effect on skin health. Thus, enhancing skin barrier function can alleviate or ameliorate skin problems, including allergies.

The composition may inhibit degranulation of mast cells or enhance skin barrier function. Specifically, when mast cell degranulation is induced, histamine may be secreted, thereby causing skin problems such as inflammation, itching, or reddening of the skin, and the composition may relieve skin barrier damage by histamine secretion. can do.

Specifically, the composition may include one or more of the following features: 1) inhibition of secretion of beta-hexosaminidase from mast cells; 2) inhibition of histamine secretion from mast cells; 3) increased expression of serine-palmitoyltransferase (SPTLC); And 4) increased expression of ceramide synthase (CerS).

Specifically, the amount of histamine released may be suppressed to 35% or more when the composition containing 20 ppm of ethyl ferulate is administered as compared to the case of administering only 50 nM of allergens and 1 μM of A23187. . In addition, when the composition containing 50 ppm of ethyl ferulate is administered, the expression of SPTLC can be promoted by 50% or more, and the expression of CerS can be promoted by 30% or more, compared with the group not administered.

In one embodiment, the composition may be to increase the expression of serine-palmitoyl transferase or ceramide synthase in keratinocytes.

The serine-palmitoyl transferase may be serine-palmitoyl transferase 1, and the ceramide synthase may be ceramide synthase 3.

In other words, the composition according to the present specification can suppress the production of allergens themselves, and contain an antagonist to the receptor of the allergens already produced and secreted as a component thereof, and thus cannot fundamentally solve the allergens. It is possible to solve the limitations of the composition for improving, alleviating or treating existing allergic diseases. Accordingly, the anti-allergic composition according to the present specification may be usefully used as a composition having excellent efficacy in preventing, improving or treating allergic diseases such as asthma, atopic dermatitis and rhinitis.

In one embodiment, the composition may comprise from 0.0001 to 5% by weight of isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof. The content of ethyl ferulate, isomer thereof, pharmaceutically acceptable salt thereof, prodrug thereof, hydrate thereof or solvate thereof contained in the composition is 0.0001. If it is less than the weight% effective anti-allergic effect is not obtained, if more than 5% by weight, there is a problem that the formulation stability is poor due to the crystallization of the active ingredient in the formulation. The ethyl ferulate, isomer thereof, pharmaceutically acceptable salt thereof, prodrug thereof, hydrate thereof or solvate thereof is preferably 0.0001 to 3% by weight, more preferably 0.001 to 2% by weight, more preferably , 0.01 to 1% by weight may be included.

In one embodiment, the composition may be a pharmaceutical composition, a food composition or a cosmetic composition.

The cosmetic composition herein is not particularly limited in formulation, and may be appropriately selected as desired.

For example, it may be prepared in the form of a solution, an emulsion obtained by dispersing an oil phase in an aqueous phase, an emulsion obtained by dispersing an aqueous phase in an oil phase, a suspension, a solid, a gel, a powder, a paste, a foam, or an aerosol composition, but It is not limited.

In addition, the cosmetic composition may further include other ingredients in addition to the above-mentioned substances within the range of not impairing the main effect, preferably synergistic effect on the main effect. In addition, the cosmetic composition may further include a moisturizer, an emulsifier, a UV absorber, a preservative, a fungicide, an antioxidant, a pH adjuster, organic and inorganic pigments, fragrances, coolants or limiting agents. The compounding quantity of the said component can be easily selected and used by those skilled in the art within the range which does not impair the objective and effect of this specification.

In addition, the food composition may further include other ingredients and the like that can give a synergistic effect to the main effect within a range that does not impair the main effect of the active ingredient. For example, it may further include additives such as perfumes, pigments, fungicides, antioxidants, preservatives, moisturizers, thickeners, inorganic salts, emulsifiers and synthetic polymer materials for improving the physical properties. In addition, it may further include auxiliary components such as water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides and seaweed extract. The components may be appropriately selected and blended by those skilled in the art according to the formulation or purpose of use, and the amount of the additives may be selected within a range that does not impair the purpose and effect of the present specification.

In the present specification, the pharmaceutical composition may be to include an external composition for skin. The formulation of the pharmaceutical composition may be, but is not limited to, solutions, suspensions, emulsions, gels, drops, suppositories, creams, ointments, patches, pads or sprays. The formulations can be readily prepared according to conventional methods in the art, and include excipients, hydrating agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, colorants, spices, stabilizers, preservatives, preservatives or other compatible agents. Adjuvants may be used as appropriate.

Its daily dosage may be, for example, 0.1 mg / g / day to 100 mg / g / day, more specifically 5 mg / g / day to 50 mg / g / day, but is not limited thereto. .

The composition may preferably be oil-in-water, and in one embodiment may be an oil-in-water cream formulation.

Cream formulation according to one embodiment is shown in Table 1 below.

ingredient	Content (wt%)
Disodium ID	0.02
glycerin	5.00
Butylene Glycol	5.00
Carbomer	0.30
Glyceryl Monostearate	1.50
Fiji-40 Stearate	1.00
Cetearyl Alcohol	1.50
Sorbitan stearate	0.50
Hydrogenated Polydecene	4.00
Cetylethylhexanoate	5.00
Dimethicone	1.00
Phenoxyethanol	0.50
Ethyl ferulate	0.20
Water	To 100

Hereinafter, the configuration and effects of the present invention will be described in more detail with reference to Examples and Test Examples. However, these examples and test examples are provided only for the purpose of illustration in order to help the understanding of the present invention is not limited to the scope and scope of the present invention by the following examples.

Example 1 Confirmation of Anti-allergic Effect of Ethyl Ferulate Experiment-Inhibition of Secretion of Allergens in Granules of Mast Cells

Example 1-1 Inhibition of Activity of Beta-Hexosamidinase

Allergen PMA (Phorbol 12-myristate 13-acetate) and Calcium Ionophore A23187 were mixed at 50 nM and 1 μM, treated with mast cells, and ethyl ferulate was concentrated (12.5 ppm, 25 ppm, 50 ppm, 100 ppm) was determined by measuring the activity of beta-hexosaminidase, a marker of degranulation, and the activity of beta hexosaminidase was determined by p-nitrophenyl-acetyl-β-D-glucosanamide. (p-nitrophenyl-acetyl-β-Dglucosaminide) was determined as the amount of p-nitrophenol liberated. The group not treated with the allergen was designated as a negative control group (without PMA), and the group treated with the allergen alone was designated as a positive control ((-) Con).

As a result, as shown in Figure 1, ethyl ferulate was shown to inhibit the secretion of beta hexosaminidase, a marker of mast cell degranulation. Accordingly, it was confirmed that ethyl ferulate has an excellent effect of inhibiting the secretion of allergens present in the granules of mast cells.

Example 1-2 Histamine Secretion Inhibition Activity

RBL-2H3 cells (purchased from Korea Cell Line Bank) were inoculated in 96 well plates at a concentration of 2.5 × 10 ⁵ cells / well and cultured. After cell adhesion, ethyl ferulate was treated in Tyrodes's buffer (10 mM Hepes, 130 mM NaCl, 5 mM KCl, 1.4 mM CaCl2, 1 mM MgCl2, 5.6 mM glucose, and 0.1% BSA, pH 7.4) for 24 hours. Incubated. After adding 50 nM PMA and 1 μM of A23187, the reaction was carried out in an incubator for 1 hour, and the supernatant was recovered to determine whether the histamine release was inhibited. Histamine release was measured according to the method of histamine kit (cisbio assays).

As a result, ethyl ferulate inhibited histamine secretion at least 37% or more, it was confirmed that it is effective in improving allergy (Fig. 2).

Example 2 Confirmation of Skin Barrier Function Improvement Effect

Human keratinocytes (HaCaT) were incubated in medium containing 10% FBS, 1% penicillin / streptomycin, and then placed in each well so that the concentration of cells in a 6-well plate was 1 × 10 ⁵ cells / well. After inoculation, the cells were incubated for 48 hours, and ethyl ferulate was added for each concentration to incubate for 24 hours. Used with untreated control for evaluation, after the reaction was completed, the supernatant was collected, the cells were washed with PBS (Phosphate Buffer Saline), the cells were collected and recovered according to the PureLink® RNA Mini Kit (ambion by life technologies) method. mRNA was extracted. Thereafter, cDNA was synthesized according to the High Capacity RNA-to-cDNA Kit (Applid Biosystems) method, and test cells and control cells were analyzed by real time PCR to analyze CerS3 and SPTLC1 gene expression levels. Primer information used for PCR is as described in Table 2 below.

Primer type	order
CerS3 (Forward)	TGG TTC TGG TCG GAG AGA TAC TGG C
CerS3 (Reverse)	GAA GCT CAT CAG ACT AAT AGC AGC C
SPTLC1 (Forward)	TGG AAG AGA GCA CTG GGT CT
SPTLC1 (Reverse)	GCT ACC TCC TTG ATG GTG GA

As a result, when treated with ethyl ferulate, the expression of serine-palmitoyl transferase and ceramide synthase 3, which directly affects the promotion of ceramide synthesis, was promoted at least 50% and at least 25%, respectively. It was confirmed that it is effective in improving the function (FIGS. 3 and 4).

Claims (6)

1. An allergy alleviating composition comprising ethyl ferulate, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof as an active ingredient.
2. The method of claim 1,

   The composition,

   A composition for allergy alleviation, which inhibits degranulation of mast cells or enhances skin barrier function.
3. The method of claim 2,

   The composition, allergic composition comprising one or more of the following features:

   1) inhibition of secretion of beta-hexosaminidase from mast cells;

   2) inhibition of histamine secretion from mast cells;

   3) increased expression of Serine-Palmitoyltransferase; And

   4) Increased expression of Ceramide Synthase.
4. The method of claim 1,

   The composition, allergic relief composition comprising 0.0001 to 5% by weight of the ethyl ferulate, isomer thereof, pharmaceutically acceptable salt thereof, prodrug thereof, hydrate thereof or solvate thereof.
5. The method according to any one of claims 1 to 4,

   The composition,

   Allergy relief composition, which is a pharmaceutical composition, a food composition or a cosmetic composition.
6. The method of claim 5,

   The composition is an oil-in-water type, allergy relief composition.

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